Benzodiazepines belong to the hypnotic-sedative class of drugs which have anxiolytic, sedative, and hypnotic properties. These drugs have been in clinical use for at least half a century. The propensity for development of dependence, especially on prescription benzodiazepines, coupled with the risk of falls and cognitive impairment due to benzodiazepines makes the elderly population susceptible to adverse outcomes with the use of benzodiazepines, and hence, cautious use is desired in this population. This review discusses the various aspects pertaining to benzodiazepine abuse in the elderly including pharmacology, prevalence of abuse, adverse consequences of benzodiazepine abuse, and subsequently assessment and management of elderly patients with benzodiazepine abuse.

Benzodiazepines belong to the hypnotic-sedative class of drugs. [1] They have anxiolytic, sedative, hypnotic, anticonvulsant, and amnesic properties owing to their action on the gamma amino butyric acid (GABA) receptors in the central nervous system. After the serendipitous discovery of the molecule chlordiazepoxide in 1955, benzodiazepines quickly became widely prescribed drugs. This happened due to them being less toxic than barbiturates and a safer choice than the other sedative agents being used at the time. [2],[3] However, in the 1980s, concern regarding abuse of benzodiazepines grew and this led to formulation of guidelines and even legislation so as to regulate prescription of benzodiazepines.

One section of population who was noted to be particularly vulnerable to the risks associated with benzodiazepines use was the elderly. [4] The propensity for development of dependence, especially on prescription benzodiazepines, coupled with the risk of falls and cognitive impairment due to benzodiazepines makes the elderly population susceptible to adverse outcomes with the use of benzodiazepines. This review discusses the various aspects pertaining to benzodiazepine abuse in the elderly including pharmacology, prevalence of abuse, adverse consequences of benzodiazepine abuse, and subsequently assessment and management of elderly patients with benzodiazepine abuse.

Pharmacology of benzodiazepine use in the geriatric population

GABA is the most common inhibitory neurotransmitter in the central nervous system. GABA neurotransmission plays an important role in modulating the excitatory activity of the brain. [5] Benzodiazepines act as positive allosteric modulators predominantly on the GABA type A (GABA-A) receptor. The GABA-A receptor is a ligand-gated chloride-selective ion channel and it is made up of 5 subunits (2 α, 2 β, and 1 γ). [6] Benzodiazepines bind to a pocket between α and γ subunits and induce conformational changes in the receptor that leads to increased binding of GABA to the receptor and increased chloride channel activity. Chronic usage of benzodiazepines leads to lowered GABA receptor activity and alters the activity of other neurotransmitters in the brain as well. [7],[8] Evidence suggests that age is associated with greater sensitivity of GABA receptors to benzodiazepines. [9],[10] Due to aging, certain structural and functional changes occur in the brain, such as neuronal loss, reduced density of dendritic synapses, glial cell proliferation, and reduced intercellular enzymes. These changes might be the causes of greater sensitivity of the aging brain to the effects of benzodiazepines.

Pharmacokinetics of benzodiazepines in elderly depends on certain age-related and drug-related factors. [11][Table 1] illustrates the various age-related changes and their pharmacokinetic implications. [12],[13],[14] Drug's route of administration (oral, sublingual, intranasal, intravenous, intramuscular, or rectal), lipid solubility, plasma protein binding, and molecular size are the drug-related factors that determine the volume of distribution of the drug. Most benzodiazepines are rapidly absorbed orally and the more lipophilic molecules cross the blood-brain barrier to quickly exert central nervous system effects. Termination of effect of benzodiazepines takes place due to redistribution of the drug to peripheral tissue. Metabolism of benzodiazepines takes place in the liver by oxidation and conjugation with glucuronide prior to excretion in urine. Cytochrome enzymes such as CYP 3A4, CYP 2E1, and CYP 2C9 catalyze the oxidation reactions. Since several drugs can alter the activity of these cytochrome enzymes, polypharmacy in geriatric population often leads to adverse drug-to-drug interactions. Some benzodiazepines have a significantly longer duration of action due to various active metabolites that have half-lives (for example, nor-diazepam has half-life of 50-180 h). Accumulation of these longer acting metabolites due to impaired hepatic metabolism, renal insufficiency, and other pharmacokinetic disturbances could lead to toxicity. Due to these factors, the ideal method of prescribing benzodiazepines in elderly is to "start low and go slow." Further, drugs with a shorter half-life and those that do not undergo oxidative metabolism (e.g. lorazepam, temazepam) may be preferred. [15] Thus, the duration of action and potency of action determine the safety profile of benzodiazepines. [Table 2] classifies the benzodiazepines according to these parameters into high-potency and low-potency benzodiazepines, which determine their clinical profiles. Benzodiazepines are prescribed in different dose ranges for different indications. The high-potency, short-acting drugs are used on a short-term basis to treat panic disorder, anxiety, and insomnia. Long-acting agents are useful for initial management of anxiety, insomnia, and treating epilepsy. They are the preferred agents for alcohol and sedative/hypnotic withdrawal.

Table 1: Age-related pharmacokinetic changes in the body and their effect on benzodiazepine metabolism

It has been remarked that benzodiazepines have a tendency of being abused. [16],[17] It has been suggested that drugs with high potency and short half-lives have a higher likelihood of being abused. The drugs with high potency include alprazolam, lorazepam, and clonazepam while those of low potency include oxazepam, temazepam, chlordiazepoxide, nitrazepam, and diazepam.

Duration of use and individual-related factors are the other characteristics that determine abuse potential of benzodiazepines. There are four important determinants of abuse potential of sedative-hypnotic agents: [18] Strong euphoric or mood altering effects; tolerance to primary therapeutic effect; rapid onset and rapid termination of action; and presence of withdrawal symptoms upon dose reduction or drug discontinuation.

Prescription databases offer further real-world insights into abuse liability of benzodiazepines. [19] Using data from overlapping prescriptions from different prescribers, it was seen that flunitrazepam has greater abuse potential as compared to diazepam, which had greater abuse potential than alprazolam and clonazepam. Collation of data from other sources also suggests that diazepam has higher abuse liability as compared to alprazolam and clonazepam, which in turn has higher abuse liability as compared to chlordiazepoxide. [20]

Prevalence of benzodiazepine abuse in the elderly

Benzodiazepines have been prescribed among the elderly population primarily for its anxiolytic and hypnotic properties. There are extensively used in geriatric psychiatry, and they are popular because they can be used on an immediate basis to quell panic attacks, intermittent anxiety symptoms, and for acute management of insomnia. [9],[21] An observation of benzodiazepines use trends during the period 2001-2010 among geriatric age group attending emergency clinics in the USA shows that benzodiazepines use has been consistent among this age group during the decade. Its use has increased from 8.9% to 19.3% among those aged 85 and above. [22] Trend reports from Australia of the 20-year period between 1992 and 2011 indicate a 29.4% drop in the quantity of benzodiazepines utilized during this period. Records indicate an increase in number of pills prescribed per prescription and an increased prescription of alprazolam. [23] Another study that recorded trends of benzodiazepine use among general Australian population during the period 2003-2006 reported a 2% decline in benzodiazepines use during this time. [24] Both these studies reported a high use of benzodiazepines among the population aged more than 65 years, with the highest consumption being by those aged more than 85 years. The older age group reportedly uses a higher quantity of hypnotics. A systematic review of epidemiological data explored long-term use of benzodiazepines in Europe for the period 1994-2014. It shows the overall long-term prevalence of benzodiazepines use to be 3% in the general population. [25] The estimates are dramatically higher for the elderly population (47%) and it often exceeds the daily-recommended dosages in this group. A longitudinal observation of benzodiazepine use trends in a city in the UK showed that those aged between 60 and 70 years had 10%, 6%, and 7% rate of episodic, recurrent, and chronic use of benzodiazepines, respectively. [26] The chronic users of benzodiazepines had significant cognitive decline. An observational study recorded inappropriate benzodiazepine use in Norway's geriatric population aged 70-89 years during the year 2008. [27] Inappropriate use was quantified as anxiolytic benzodiazepine use/hypnotic Z-drug use for more than 30 weeks or hypnotic benzodiazepines use exceeding 300 daily drug dosage for the year or 9 daily drug dosage per week. Widespread inappropriate usage was recorded among 25% of anxiolytic benzodiazepine users, 100% of hypnotic benzodiazepine users, and 65% of Z-hypnotic users. The prevalence was 12.3% in the elderly source population. An assessment of chronic benzodiazepine use among elderly people in Belgium shows that the actual daily dose of both anxiolytic and hypnotic benzodiazepines more often than not exceeds the geriatric upper age limit. [28] A cross-sectional assessment of sedative drug usage among a randomized community sample of elderly people from Finland shows the use of more than one sedative agent by 29% of the sample. [29] Two or more sedative agents are more likely to be used by females, more by those with impaired functioning and psychological problems.

Several research studies from India have documented the occurrence of benzodiazepine dependence or abuse in the elderly. A retrospective cross-sectional study reporting the pattern of use of psychotropics by elderly patients presenting to a tertiary care psychiatric outpatient department in India found that benzodiazepines were the most commonly prescribed drug, being prescribed in 64% of the sample. [30] Grover etal. [31] reported that benzodiazepines were prescribed to patients across diagnostic groups in elderly outpatients, with clonazepam being the most frequently prescribed followed by lorazepam. A case series also highlights several patients with dependence and delirium among elderly patients who have been prescribed zolpidem. [32]

Adverse events of benzodiazepine abuse in elderly

Among those aged 65 years and older, epidemiological studies also show a higher risk of adverse effects such as those listed in [Table 3]. [17],[33],[34],[35],[36],[37],[38] Another aspect regarding benzodiazepines associated adverse effects in the elderly is the greater incidence of respiratory failure, aspiration pneumonia, coma, and death due to benzodiazepines overdose. [39] The elderly population using benzodiazepines is more likely to experience delirium. The risk to develop this life-threatening condition is further aggravated in the presence of other cardiovascular complications and metabolic disturbances. [40]

Systematic reviews and meta-analyses have attempted to collate the data on the risk and benefit of benzodiazepines in the elderly. Glass etal. [41] analyzed data from 24 studies and found that while sleep quality improved, there was increased risk of cognitive impairment (odds ratio [OR] of 4.78), psychomotor impairment (OR 2.61), and daytime fatigue (OR 3.82) with benzodiazepines as compared to placebo. A meta-analysis of 10 studies by Sithamparanathan etal. [33] suggested that risk of adverse effects due to benzodiazepines use among elderly people found to be 2.45 times than in general population. Hartikainen etal. [42] found that the benzodiazepines were a prominent risk factor for falls among the elderly. Barker etal. [43] analyzed 13 studies assessing the neuropsychological effects of benzodiazepine use and found that long-term use of benzodiazepines was associated with neuropsychological deficits. The effect sizes of score deficits on neuropsychological tests ranged from −1.30 to −0.42.

Billioti de Gage etal. [44] reported an increased risk of dementia with benzodiazepines, risk being greater for longer acting molecules, greater duration of treatment, and higher dosages. Several recent large-scale studies have attempted to find the relationship between benzodiazepine use and occurrence of dementia. [45],[46] While benzodiazepine use was found to be associated with slightly higher rates of developing dementia, a dose-response relation was not found and higher doses of benzodiazepines were not associated with increased rates of dementia. [45] Another follow-up study on similar lines suggested that benzodiazepine use was associated with about 10% increased rates of developing dementia, [46] and the risk of dementia was higher with benzodiazepines with longer half-lives as compared to benzodiazepines with shorter half-lives. Several mechanisms have been proposed to underlie the increased risk of development of dementia in patients with benzodiazepine dependence: [47] astrocytes in the area of amyloid plaques could have GABA-secreting activity, making patients with predementia lesions more vulnerable to cognitive effects of benzodiazepines, and lowering the neural compensation and cognitive reserve for coping with initial neurological lesions using/developing alternative networks.

Aspects of benzodiazepine dependence among the elderly

Benzodiazepine use could lead to physiological and psychological dependence depending on certain drug-related factors such as dosage of the drug, their duration of action, and potency. [17] Both the physiological and psychological components play a role in the genesis of dependence toward benzodiazepines. [48],[49]

Benzodiazepine dependence has been classified into three overlapping kinds by Ashton: [50]

Therapeutic-dose dependence: It occurs when benzodiazepines prescriptions have been continued for inordinately long periods. Elderly people with comorbid physical and mental illness or those in old-age homes are usually chronic prescribed benzodiazepines users. Iatrogenic dependence on benzodiazepines could occur following stay in an intensive care unit [51]

Prescribed high-dose dependence: Individuals with this kind of dependence include those who have been initiated on benzodiazepines use by medical prescriptions but have escalated amount used on their own. This pattern of dependence is prevalent among the elderly population

Recreational benzodiazepines abusers: Elderly with recreational use of benzodiazepines usually have comorbid substance use disorders. Ignoring multiple substance use among the elderly can have serious consequences due to chronic use and due to inadequate withdrawal management.

Keeping in mind the adverse outcomes associated with prolonged benzodiazepine use and the known determinants of abuse, various patterns of abuse found among elderly population certain guidelines need to be followed while prescribing benzodiazepines to the elderly. [Table 4] outlines the do's and don'ts of prescribing of benzodiazepines. Following these could help in rational use of benzodiazepines in the elderly and avoid the occurrence of benzodiazepine dependence.

Table 4: Do's and Don'ts of prescribing benzodiazepines to the elderly

Research on aspects related specifically to management of benzodiazepine abuse in the elderly is limited. Lack of validated screening tools prevents inclusion of the at-risk population into treatment. Management of acute withdrawal symptoms is an important part of treatment plan for those dependent on benzodiazepines. Management begins with an assessment of the elderly patient for signs of abuse/dependence and presence of other psychiatric, physical, substance use-related comorbidities through clinical history taking and a thorough physical and mental state examination. [52],[53] As a screening tool, Alcohol, Smoking and Substance Involvement Screening Test is useful to look for drug misuse by the elderly. [54] Necessary laboratory-based and radiological investigations should be carried out. This is followed by therapeutic interventions for withdrawal symptoms and long-term management. [Figure 1] provides a basic outline of management.

Figure 1: Assessment and treatment of an elderly patient with benzodiazepine abuse/dependence

Discontinuation of benzodiazepines or reduction of dose results in emergence of withdrawal symptoms among users. Most withdrawal symptoms subside within 5-28 days with a peak in severity at 2 weeks following withdrawal from the drug. [55][Table 5] enlists the acute withdrawal symptoms experienced by benzodiazepine users. However, there may be an occurrence of a "postwithdrawal syndrome" or protracted withdrawal months after stopping benzodiazepines use in some patients [Table 5]. [50]

Management of acute withdrawal symptoms is an important part of treatment plan for those dependent on benzodiazepines.

The pharmacological management of benzodiazepines withdrawal is centered on gradual tapering of the total daily dose of benzodiazepines over successive days

Systematic dosage reduction using equivalent doses of long-acting benzodiazepines such as diazepam helps in mitigating the withdrawal symptoms to a great degree. [56] The equivalent doses of benzodiazepines have wide ranges due to pharmacokinetic differences between various benzodiazepines. Hence, physicians should settle on an equivalent dose on which the patient is comfortable. While some patients may be able to tolerate a rapid dose reduction, others may need a more gradual taper

The dose is usually reduced by 25% every week; the tapering off might need to be further slowed down during the last few dosage reductions. Most guidelines suggest a 4-8 weeks discontinuation schedule [57]

A benzodiazepine withdrawal schedule should be individualized to patient's needs, with larger dose reductions in the initial phase [58]

Another approach is to gradually reduce the dose of the benzodiazepine being used

Adjuvant medications such as carbamazepine, gabapentin, β-adrenergic receptor antagonists, and valproate could also be used if indicated. Use of some off-label medications such as flumazenil and pregabalin has also been suggested [59]

A decision about inpatient or outpatient management can be made depending upon severity of withdrawals and presence of any life-threatening withdrawal symptom

Inpatient treatment is recommended in case of an underlying medical/psychiatric comorbidity, history of failed treatment attempts, and patient preference

Nonpharmacological approaches are an important component of managing withdrawal symptoms, especially in the elderly. These include cognitive restructuring and cognitive behavioral strategies so as to help patient feel that they have control over their withdrawal symptoms and to manage anxiety [60],[61]

Nonpharmacological interventions also include interventions to prevent maladaptive behaviors such as increased alcohol/other psychoactive substance use and use of other sedative/hypnotic agents (Z-drugs, barbiturates).

Long-term outcome of management of benzodiazepines in elderly population

Long-term strategies include using better alternatives to manage symptoms of anxiety and insomnia for which benzodiazepines might have begun to be prescribed in the first place.

Nonpharmacological interventions such as relaxation training, cognitive behavioral therapy, supportive therapy, and cognitive therapy are evidence-based treatments for anxiety disorders and insomnia in the elderly population [63],[64]

Alternative medications to manage insomnia include sedating antidepressants such as trazodone, mirtazapine, amitriptyline, nefazodone, doxepin, clonidine, quetiapine, or judicious use of nonbenzodiazepine sedatives such as zaleplon, zolpidem, and eszopiclone [65],[66],[67]

Measures taken to manage protracted withdrawal symptoms are also included in long-term pharmacological and nonpharmacological interventions

It is also recommended to educate adults aged 65 years and older about the harms associated with continued use of benzodiazepine and to encourage them to gradually discontinue prescription refills of benzodiazepines and avoid new benzodiazepines prescriptions [68]

From the clinician's perspective, use of certain criteria and tools could help with tracking of inappropriate prescription of medications to elderly patients. The beers criteria are one such tool that can help avoid use of benzodiazepines in elderly population except for those under hospice/palliative care. [69] Another such criteria are the Screening Tool of Older Person's potentially inappropriate Prescriptions and Screening Tool of Alert doctors to the Right Treatment criteria which have proven to be useful. [70],[71],[72]

Conclusion

Benzodiazepine use is quite frequent among the elderly population. They are popular as anxiolytic and hypnotic agents. Commonly, use among the older adults usually begins with a prescription and which then could lead to inappropriate use. The adverse effects due to benzodiazepines use are higher in the geriatric population due to age-related pharmacokinetic and pharmacodynamic changes that occur in the body. Polypharmacy and presence of comorbid medical disorders among the geriatric population also play a part in causing complications due to benzodiazepines use among the elderly. Thus, their use is no longer recommended among the geriatric population. The adverse effect profile of benzodiazepines in older people includes cognitive and motor impairment. Management of withdrawal symptoms caused due to termination of benzodiazepines use involves tapering of the benzodiazepines and/or use of adjuvant medication. Nonpharmacological interventions play an important role in withdrawal management. Long-term pharmacological and nonpharmacological therapy is essential for treating the anxiety and insomnia that chronic users of benzodiazepines have to deal with. Clinicians should exercise caution when prescribing medications to the elderly and monitor use of benzodiazepines to look for adverse effects and misuse of the drug.